Project Summary Hearing loss is an exceedingly common and debilitating chronic health condition, with over 30 million individuals 12 years and older suffering from bilateral hearing loss in the United States. Auditory dysfunction has been linked to social isolation, depression, dementia, and increased mortality; however, many gaps persist in our understanding of the pathophysiology of this condition. Small observational studies have suggested there may be a link between chronic kidney disease (CKD) and hearing loss, with 36% to 77% of individuals with CKD having at least mild sensorineural hearing loss. The cochlea and the kidney share anatomic and physiologic similarities, with many of the same pumps, channels, and ATP-ases expressed in both the renal tubular cells and the inner ear. Animal models also suggest there is an inverse correlation between serum creatinine levels and Na+/K+ ATPase activity in the ear, and therefore inhibition of ATPase activity by impaired renal function may promote inner ear dysfunction. There are no longitudinal studies that have assessed the relation between chronic kidney disease and hearing loss. Furthermore, there are no data that delineate how hearing thresholds change before and after renal transplant, once a uremic state has been corrected. We therefore propose to highlight a potential causal association between hearing loss and CKD. In Aim 1, we will conduct a prospective cohort study to assess whether reduced renal function is associated with an increased risk of hearing loss. We will utilize the Epidemiology of Hearing Loss Study, a longitudinal cohort study that has assessed the incidence and progression of hearing loss. Renal function was measured at two different time points in 1847 participants, and pure tone audiometry was conducted at baseline and every 5 years thereafter. We will use baseline and subsequent measurements of estimated glomerular filtration rate (eGFR) divided into categories to compare the risk of incident hearing loss. We hypothesize that those participants with a lower baseline eGFR, and those with a rapid decline in eGFR over time, will have an increased risk of incident hearing loss. In Aim 2, we will conduct a prospective cohort study to determine the association between renal transplantation and auditory function before and after transplant. We will recruit recipients of living donor transplants (n=34) over one year at Brigham and Women's Hospital and Massachusetts General Hospital. We will then conduct pure tone audiometry testing within 30 days before the transplant is performed, and then at months 1, 3, 6, and 12 post-transplant. We hypothesize that transplant recipients will have improvement in their hearing thresholds 6 months post-transplant, as compared with pre-transplant. Collectively, these studies could allow for earlier diagnosis and intervention for those at highest risk of hearing loss, and potentially lead to significant improvements in quality of life for CKD patients.